chr4-3463582-CG-C

Variant names:

• chr4-3463582-CG-C
• rs566267525
• NM_173660.5:c.100+36delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.100+36delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,016,136 control chromosomes in the GnomAD database, including 154 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (81 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (73 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.429
• Publications: 0 publications found

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-3463582-CG-C is Benign according to our data. Variant chr4-3463582-CG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.100+36delG		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.100+36delG		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.100+36delG		intron	N/A	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.100+32delG		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.100+32delG		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.100+32delG		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2529 AN: 146210 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0612

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.0000905

Gnomad OTH AF: 0.00890

GnomAD2 exomes AF: 0.00325 AC: 412 AN: 126770 AF XY: 0.00236

Gnomad AFR exome AF: 0.0613

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00234 AC: 2036 AN: 869844 Hom.: 73 Cov.: 31 AF XY: 0.00187 AC XY: 829 AN XY: 442616

African (AFR) AF: 0.0800 AC: 1720 AN: 21510

American (AMR) AF: 0.00304 AC: 97 AN: 31876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18574

East Asian (EAS) AF: 0.00 AC: 0 AN: 25928

South Asian (SAS) AF: 0.000158 AC: 11 AN: 69502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22432

Middle Eastern (MID) AF: 0.00107 AC: 3 AN: 2804

European-Non Finnish (NFE) AF: 0.0000360 AC: 23 AN: 639606

Other (OTH) AF: 0.00484 AC: 182 AN: 37612

GnomAD4 genome AF: 0.0173 AC: 2538 AN: 146292 Hom.: 81 Cov.: 33 AF XY: 0.0165 AC XY: 1180 AN XY: 71430

African (AFR) AF: 0.0612 AC: 2423 AN: 39580

American (AMR) AF: 0.00601 AC: 89 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.00 AC: 0 AN: 4868

South Asian (SAS) AF: 0.000221 AC: 1 AN: 4528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9652

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0000905 AC: 6 AN: 66272

Other (OTH) AF: 0.00881 AC: 18 AN: 2042

Alfa AF: 0.00902 Hom.: 3

Bravo AF: 0.0205

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs566267525; hg19: chr4-3465309;